The Medicine by Design Global Speaker Series invites established and emerging international leaders in regenerative medicine to engage with our extraordinary community of researchers and clinicians.
Medicine by Design, in partnership with the McEwen Stem Cell Institute, is pleased to welcome Domitilla Del Vecchio, PhD, from the Massachusetts Institute of Technology.
Talk title: Synthetic genetic circuits to uncover and enforce the OCT4 trajectories of successful reprogramming of human fibroblasts.
About the Del Vecchio lab
Domitilla Del Vecchio received the PhD degree in Control and Dynamical Systems from the California Institute of Technology, Pasadena, and the Laurea degree in Electrical Engineering (Automation) from the University of Rome at Tor Vergata in 2005 and 1999, respectively. From 2006 to 2010, she was an Assistant Professor in the Department of Electrical Engineering and Computer Science and in the Center for Computational Medicine and Bioinformatics at the University of Michigan, Ann Arbor. In 2010, she joined the Department of Mechanical Engineering at the Massachusetts Institute of Technology (MIT), where she is currently Professor and member of the Synthetic Biology Center. She is a Fellow of the International Federation of Automatic Control (2022), an IEEE Fellow (2021), and a recipient of the Newton Award for Transformative Ideas during the COVID-19 Pandemic (2020), the 2016 Bose Research Award (MIT), the Donald P. Eckman Award from the American Automatic Control Council (2010), the NSF Career Award (2007), the American Control Conference Best Student Paper Award (2004), and the Bank of Italy Fellowship (2000). Her research focuses on developing techniques to make synthetic genetic circuits robust to context and on applying these to biosensing and cell fate control for regenerative medicine applications.
Reprogramming human fibroblasts to induced pluripotent stem cells (iPSCs) is inefficient, with heterogeneity among transcription factor (TF) trajectories driving divergent cell states. Nevertheless, the impact of TF dynamics on reprogramming efficiency remains uncharted. In this work, we identify the successful reprogramming trajectories of the core pluripotency TF, OCT4, and design a genetic controller that enforces such trajectories with high precision. By combining a genetic circuit that generates a wide range of OCT4 trajectories with live cell imaging, we track OCT4 trajectories with clonal resolution and find that a distinct constant OCT4 trajectory is required for colony formation. We then develop a genetic controller circuit that yields a tight OCT4 distribution around the identified trajectory. In terms of reprogramming efficiency, this controller outperforms other circuits that less accurately regulate OCT4. Our approach is generalizable for identifying and enforcing TF dynamics for cell fate programming applications.